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Chapter Outlines

Chapter 16      Human Immunodeficiency Virus (HIV)

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16.1 The History of HIV Early 1980's, U.S. Physicians in New York and California made the first observations of a new infectious disease of homosexual men. Sudden appearance of rare skin cancer called Kaposi's sarcoma Referred to as"gay cancer" Atypical pneumonia caused by Pneumocystis carinii CMV infections Candiasis Other observed opportunistic infections Gay-Related Immune Deficiency (GRID) All observed individuals suffered from immune suppression 1981 named the syndrome GRID 1982 disease renamed Acquired Immune Deficiency Syndrome (AIDS) 1983 - 2304 AIDS deaths 1985 Rock Hudson announced he had AIDS and died The Discovery of HIV 2 research teams Robert Gallo's group, NCI, NIH, U.S. Luc Montagnier's team, Pasteur Institute, France Upon investigation, Montagnier's team was the first to isolate HIV HIV-1 vs. HIV-2 HIV-1 isolated by Gallo and Montagnier's teams were designated HIV-1. Montagnier isolated another strain, that is rare in the U.S. but is endemic to Western Africa. HIV-2 HIV-2 is significantly less infectious and progresses more slowly to AIDS than HIV-1 The Origin of HIV-1 and the AIDS Pandemic House Cat theory The Hunter theory (or crossing the species barrier theory) The contaminated poliovirus vaccines theory The colonization theory (or Heart of Darkness Theory) The conspiracy theory The Hunter Theory (Most Commonly Accepted Theory) HIV is a viral zoonosis. A virus related to HIV-1, called SIVcpz which infects chimpanzees (native to Cameroon) crossed the species barrier Chimps hunted for food; a naturally infected chimp was killed for food (bushmeat) and eaten; their blood entered cuts or wounds on the hunter. Subsequently, SIVcpz adapted to become HIV-1 Where Did HIV-2 Originate? HIV-2 entered the human population as a zoonosis (like HIV-1). Sooty mangabeys are native to Guinea Bissau, Gabon and Cameroon and naturally carry SIVSM. SIVSM from sooty mangabeys (an Old World Monkey) likely evolved into HIV-2 when humans were hunting sooty mangabeys for food and through contaminated blood transfusions and mass vaccination efforts. 10% of the general population in Guinea Bissau is HIV-2 sero-positive. The AIDS Pandemic: Patient Zero vs. the Earliest AIDS Cases Who was patient zero? Randy Shilts book, And the Band Played On proposed that a homosexual French-Candian flight attendant who died of AIDS in 1984 was patient zero. HIV had been found in blood samples and frozen tissues older than the 1980's. 16.2 HIV Transmission HIV is present in blood, semen, vaginal fluids, breast milk, saliva (low levels) and tears (low levels). Most common ways HIV can be transmitted are: Anal and vaginal intercourse Sharing of contaminated needles (IV drug users) Blood transfusions (using infected blood or blood products) Accidental needlestick injuries Congenital AIDS Sharing HIV-contaminated tattoo needles, razors, acupuncture needles, ear piercing implements Can Kissing and Oral Sex Transmit HIV? Social kissing is not high-risk behavior French kissing increases risk. The risk increases if the infected person has canker sores or lesions in his/her mouth. Oral sex poses similar risks. HIV-infected T lymphocytes from semen may enter abrasions or lesions in the mouth. Ways HIV is NOT Transmitted: The Fragility of HIV in the Environment Soap and water easily disrupts HIV. HIV is highly susceptible to drying out. Contact with sweat, saliva or tears has never shown to result in transmission. Handshaking and hugging has not resulted in transmission. Mosquitoes or other insects cannot transmit HIV. 16.3 Prevention of HIV Abstinence Barrier methods (condoms) Microbiocides Preexposure prophylaxis (PREP) reduces risk Postexposure prophylaxis (PEP) reduces risk 16.4 AIDS in Africa Africa, the world's largest continent, has been hit harder by HIV/AIDs than any other region of the world. Each day in Africa: 660 people die of AIDS 8800 people are infected with the HIV virus 1400 newborns are infected with HIV virus during birth or through breastfeeding At least 12 million children have lost 1 or more parents to AIDS 16.5 General Epidemiology: HIV/AIDS in the United States Today HIV cases and deaths among adults and adolescents diagnosed with AIDS 1985-2005 Prevalence Rates for Adults and Adolescents Living with HIV infection (not AIDS) in 2005. See Figure 16-4. Proportion of HIV/AIDS Cases Among Adults and Adolescents by Sex and Transmission Category in 2005. See Figure 16-4. A Risky Workplace? AIDS in the Adult Film Industry Over 200 pornagraphic film production companies in Los Angeles County, California. At least 1200 workers engage in work-related sexual contract. Workers participate in voluntary programs that screen for HIV and other STDs. At least 62 male and 6 female porn film performers died of AIDS from 1985-2002. HIV/AIDS in U.S. Correctional Facilities Activities in prisons that pose a risk for HIV transmission: Homosexual activity Intravenous drug use Tattooing and body piercing Sharing of toothbrushes and shaving equipment Incidents of violence AIDS and Seniors 11-17% of people living with HIV in the U.S. are 50+ years old Between 1990 and 2001 cases in seniors quantupled in the U.S. 24-30% of men and women ages 60-74 report they are sexually active. Erectile dysfunction drugs such as Viagra, Cialis and Levitra which may be used by older adults has been shown to be associated with higher risk of STDs, especially HIV transmission. Barriers to HIV Diagnosis in Seniors The symptoms of chronic illnesses in older adults resembles those of AIDS: Night sweats and hot flashes Weight loss or fatigue Respiratory problems Skin rashes Flulike symptoms or diarrhea Chronic pain or numbness Early signs of dementia 16.6 Clinical Symptoms 3 Phases of HIV-1 Infection Primary HIV-1 infection The chronic asymptomatic phase of infection AIDS Primary HIV-1 Infection Period after infection but before the development of detectable antibodies against HIV-1. Signs and Symptoms of Primary HIV-Infection. See Table 16-3. The Chronic Asymptomatic Phase Neither signs nor symptoms of the disease present. This phase typically lasts an average of 10 years. Typical progressors Rapid progressors Slow progressors Long term progressors AIDS Without anti-retroviral therapy, the patient will die within 2 to 3 years. As T-lymphocyte counts decrease below 50 cells/µl, the number of opportunistic infections increases. AIDs patients also suffer from malignancies such as nonHodgkin's lymphoma. Wasting syndrome also common (a loss of more than 10% of body weight due to fever or diarrhea for more than 30 days). AIDS patients managed with antimicrobial prophylactic regimens. Opportunistic Infections Commonly Associated with AIDS. See Table 16-4 16.7 Laboratory Diagnosis of HIV HIV isolated in 1983 First commerical antibody detection tests were available in 1985 Today, most clinical labs screen for HIV-1 and HIV-2 using and ELISA test (specimen is patient blood sample) All classes of anti-HIV antibodies detected with these assays HIV ELISA test Requires 2 doctor visits 1. Blood drawing and pretest counseling 2. Test results and additional counseling if needed See Figure 5-20, Chapter 5. Other rapid HIV tests Performed by healthcare worker, tests results within 5-30 minutes e.g. done on women in labor before delivery to determine infection status patients following an accidental needlestick injury Positive ELISA tests must be confirmed by Western blot HIV Home Testing Systems FDA approved first system in 1996 Home Access HIV-1 Test System Uses simple finger prick of blood sample Place on filter paper Mail in for laboratory testing Confidential results obtained through toll-free phone number and post-test counseling is available IV Western Blot Confirmatory test to exclude false positive results (See Chapter 5, Figure 5-21) Nitrocellulose membrane is probed with patient serum If the patient has been exposed to HIV, + bands will be observed on the Western blot Mandatory Testing for HIV? ~ 1 in 4 of 1 million Americans infected with HIV don't know they are infected This group is most responsible for the spread of HIV CDC released voluntary testing guidelines that would apply to every American, ages 13-64. Genetic Variation/Groups HIV mutates rapidly 3 distinct groups of HIV-1 M (Major) group O (Outlier) group N (New) group M group is further divided into clades or subtypes: A, B, C, D, F, G, H and K 16.8 HIV Virus Life Cycle: HIV Classification and Virion Structure Retroviridae family Lentivirus genus (from Latin word lenti, for"slow") Cause slowly progressive, inflammatory diseases. HIV particles 100-200 nm icosahedron-shaped sphere surrounded by an envelope Envelope contains glycoproteins gp120 and gp41 spikes Matrix proteins located below the envelope 2 copies of genome (+) ssRNA, cellular tRNAlys bound to each genome which acts as a primer for RT Reverse transcriptase (RT, p64) and integrase (p34) bound to viral genome. Protease (p10) also found within nucleocapsid of virus particle HIV-1 Entry HIV infects CD4+ T lymphocytes and will lyse them during a productive infection HIV infects other cells but does not lyse them: Natural killer cells CD8+ killer T-cells Macrophages Cell of the nervous system (e.g. astrocytes, neurons, glial cells and brain macrophages) Dendritic cells Early course of infection: HIV infects macrophages Later in the course of infection: HIV infects T lymphocytes The rapid progression to AIDS is associated with a switch in coreceptor preference. HIV enters cells via a cellular receptor and co-receptor Major cellular receptor: CD4 present on T-lymphocytes (also present in low concentrations on macrophages) Co-receptor on T lymphocytes: CXCR4 (fusion) Co-receptor on macrophages: CCR5 HIV Entry and Uncoating gp120 of the virus interacts with CD4 Subsequently HIV gp120 and gp41 undergo a conformational change, causing a coreceptor reaction The virus anchors into the membrane of the CD4+ cell HIV gp41 changes into a coiled shape, bringing the virus and cell membrane together, allowing them to fuse, resulting in entry and uncoating Reverse Transcription of HIV RNA HIV RT binds to tRNAlys on the viral genome and initiates DNA synthesis Refer to Chapter 10 (retroviral genome replication) When reverse transcription is complete, the final product is dsDNA flanked by LTRs at each end of the viral genome. The viral DNA is transported to the nucleus of th ecell where the viral genome may be integrated into the host cell's chromosomal DNA. HIV Proviral Integration Proviral integration is catalyzed by the integrase (p32) protein. p32 is packaged in the original HIV particle. HIV can latently infect cells. The latent reservoirs are one of the main barriers to elimination of HIV infection. During a production infection, HIV-1 is reactivated and the completion of the life cycle occurs. HIV Viral Genome is More Complicated than a Typical Retroviral Genome. See Figure 16-13. HIV-1 Transcription HIV-1 utilizes the host cell's transcription and translational machinery. The proviral DNA is transcribed from a single promoter in the 5' LTR into a 9 kb viral RNA transcript by the cellular RNA polymerase II HIV-1 tat and rev regulate gene expression HIV-1 Structural Gene Products and their Functions. See Table 16-5. HIV-1 Regulatory Gene Products and Their Functions. See Table 16-6. HIV-1 Accessory Gene Products and Their Functions. See Table 16-7. HIV-1 RNA Cis-Acting Elements. See Table 16-8. HIV-1 TAR TAR is located at the 5' end of all HIV RNAs. The binding of tat to TAR increases the transcription rate from the HIV LTR at least 1000 fold. Rev binds to the RRE element, facilitating the export of unspliced and incompletely spliced viral RNAs from the nucleus to cytoplasm Some full-length viral mRNAs are packaged into virions following transport into the cytoplasm. Other viral mRNAs are spliced within the nucleus to from mRNAs that are translated into the different viral proteins. HIV Accessory Proteins Nef, vif, vpu, vpr play a role in virulence. Translation of HIV Proteins Gag gene and the gag and pol genes together are translated into 1 large precursor polyprotein cleaved by a viral encoded protease Full-length env, gp160 is transported through the golgi where it is glycosylated and cleaved by a cellular protease into gp120 and gp41 to form mature envelop proteins Mature gp120 and gp41 are targeted to the surface of the infected cell. HIV-1 Assembly HIV-1 virion components (e.g. the viral RNA, gag, pol, and env proteins) are assembled at budding sites located at the cellular plasma membrane. The gag and gag-pol proteins are cleaved by an HIV specific protease to form mature virus particles. HIV Virus Life Cycle Overview. See Figure 16-14. HIV Cellular Pathogenesis Ultimately, HIV causes AIDS by depleting CD4+ T helper lymphocytes. Weakening of the immune system Body can't stop infections or remove cancer cells Opportunistic infections HIV causes syncytia formation AIDS dementia complex Occurs in 20% of infected individuals Symptoms: Impairment of cognitive reasoning (e.g short term memory problems and concentration Behavior changes (apathy, withdrawal, irritability, depression, personality changes) Motor performance (clumsiness, tremors, leg weakness) 16.9 HIV Human Genetics/Resistance: The Smallpox Hypothesis Individuals who are homozygous for a defective CCRdelta32 gene are virtually resistant to HIV infection (two defective copies are inherited, one from each parent) Individuals who are heterozygous for the defective CCR5delta32 gene progress more slowly to AIDS (only 1 defective copy inherited) CCR5delta32 CCR5 gene is missing 32 base pairs Codes for a truncated protein that is not detected on the cell surface. HIV gp120/gp41 cannot attach to it to infect cells HIV Resistance: Population Statistics European populations 5-14% heterozygous CCR5delta32 1% homozygous in some populations such as Caucasian North Americans The CCR5delta32 allele is almost absent in African, Asian, Native American Indian and Middle Eastern populations. Where Did the Resistance Allele Come From? Chemokine receptors play a central role in the immun response against many pathogens. Time is needed for natural selection to increase the frequency of a rare allele. People with CCR5delta32 survive without immune system problems because other chemokines compensate for CCR5 (e.g. CXCR4 or CCR2) Major infectious diseases in history Bubonic plague Smallpox Syphilis Tuberculosis Popular Theory CCR5delta32 led to increase survival during smallpox outbreaks that occurred in 14th-century Europe During this time, smallpox oubreaks were ongoing, allowing for continuous natural selection The CCR5delta32 genetic variant was an unintended but welcomed consequence of HIV resistance. Variola has a SECRET Variola virus encodes a 35 kd secretory protein that binds to several CC-chemokine receptors. The C-terminal of the 35 kd protein contains smallpox virus encoded chemokine receptor (SECRET) domain Acts as a chemokine inhibitor, allowing the virus to evade the immune system. In turn, individuals with a defective chemokine receptor would resist these effects by variola and HIV. 16.10 Managing HIV Patients: Antiviral Therapy CD4+ T Lymphocyte Counts Less than 200 per ml plasma Virus load monitoring Used to make recommendations for antiviral treatment of patients Measure HIV-1 RNA copies per ml of plasma 100,000 copies per ml of plasma = clinical AIDS An absence of detectable RNA copies suggest a slower progression to AIDS HIV Antiviral Therapy Zidovudine (AZT), a thymine analog, RT inhibitor first approved HIV-1 treatment Drug resistance to AZT emerged 1996 David Ho, HAART, Highly Active Retroviral Therapy - use of at least 3 compounds simultaneously to block HIV RT, protease, entry/fusion, integrase etc. 5 Classes of HIV Patients: Antiviral Therapy Nonnucleoside or nucleoside reverse transcriptase (RT) inhibitors of HIV RT Protease inhibitors that inhibit HIV maturation by blocking an HIV-specific protease, resulting in noninfectious virus Fusion inhibitors that block HIV fusion of viral gp41 protein and the host cell membrane Integrase inhibitors block HIV p32 activity, abolishing integration of the proviral DNA copy of HIV into the host cell chromosome CCR5 blocking inhibitor Progression of HIV Infection Based on T-Cell Counts and Viral Loads. See Figure 16-18. 16.11 Is an HIV Vaccine Possible? Still no HIV vaccine An AIDS patient harbors 100 million genetically distinct variants of HIV HIV variants can escape both antibody and T-cell immune responses. Will a vaccine be able to cope with this variability? The HIV Virion is More Complicated Than Portrayed in Most Textbooks HIV particles carry numerous host-derived proteins within the HIV envelope Many serum proteins are bound to the HIV particle Many of the original gp120 spikes have been lost This interferes with host antibody responses toward the virus.